The overall objective of the proposed project is to investigate the potential of the gasotransmitter carbon monoxide (CO) as an anti-inflammatory agent in Sickle Cell Disease (SCD) using a novel oral formulation of CO (HBI-002). Numerous studies, both in vitro and in vivo, demonstrate that CO has cytoprotective properties through anti-oxidant, anti-inflammatory and anti-apoptotic processes. Researchers found in three studies using four different transgenic sickle cell mouse models that the heme oxygenase-1/CO pathway is key in SCD and demonstrated that very low doses of CO are a novel approach to limiting vascular stasis and down-regulating the inflammatory process. These studies provide compelling support for a potential beneficial role for CO in limiting the morbidity of SCD. Moreover, Phase 1 clinical studies of CO in both normal volunteers and SCD patients using a variety of CO delivery mechanisms have demonstrated the tolerability and safety of CO, suggesting that the very low targeted levels of COHb will not be associated with adverse outcomes. HBI-002, an oral liquid formulation, is being developed for the treatment of SCD. The oral administration of a defined dose of CO delivered by HBI-002 obviates the problems associated with previously studied inhaled or carrier-metal CO administration, enabling the potential for the necessary chronic, safe, non-toxic outpatient dosing of CO. HBI-002 comprises CO in a water-based solution of proprietary excipients to maximize CO content. Proof-of-concept manufacture of HBI-002 has been demonstrated. Pharmacokinetic and pharmacodynamic studies in rats and in two adult healthy volunteers have demonstrated proof-of-concept feasibility, tolerability, and bioavailability. The next step in development is to demonstrate that CO delivered from HBI-002 improves outcomes in an appropriate SCD animal model and to determine the minimum effective dose in SCD mice to inform dosing in planned clinical trials.
This application aims to determine whether, and the dose at which, HBI-002, an oral carbon monoxide (CO) therapeutic, improves outcomes in an animal model of Sickle Cell Disease (SCD). HBI-002 represents an innovative means of delivering the gasotransmitter CO that has the potential for chronic, safe, non-toxic in-home use, with exact dosage in contrast to the currently available means of CO delivery. If successful, the proposed project will provide critical proof-of-concept and dosing information for further development of HBI- 002 in SCD, with the ultimate objective being to provide a therapeutic to reduce the incidence of vaso-occlusive crises and inflammation and thus reduce the incidence of disability and premature mortality in this devastating disease.
|Gomperts, Edward; Belcher, John D; Otterbein, Leo E et al. (2017) The role of carbon monoxide and heme oxygenase in the prevention of sickle cell disease vaso-occlusive crises. Am J Hematol 92:569-582|